Stem cells in vivo reside in a complex microenvironment that presents them with numerous signaling factors that regulate their behavior and functions, and understanding how these factors influence stem cell fate is a major challenge of cell and developmental biology. Designing strategies to control cell behavior is therefore critical for both fundamental studies of stem cell biology from development through adulthood, as well as for applications of stem cells in tissue engineering and regeneration. The objective of this proposal is to design novel biomaterials that modulate and control stem cell behavior. Specifically, these well-defined, biomimetic ligands and surfaces will control the activation of signaling pathways that regulate the differentiation or proliferation of neural stem cells (NSCs). We have chosen NSCs as an effective cellular system to investigate the basic biological mechanisms of stem cell control, to explore their biomedical potential, and to evaluate the promise of hybrid biological-synthetic materials for controlling the multitude functions of a stem cell in culture. The NSC mitogen Sonic hedgehog and the Notch ligand Delta will be grafted onto both soluble liposomes and synthetic surfaces to modulate cell proliferation and differentiation. This proposal will explore the structure-activity relationships of these synthetic cellular effectors. The effects of effector valency, dimensions, fluidity, and dosage on receptor clustering, signal transduction, cell proliferation, and cell differentiation will be studied. Our Specific Aims are: 1. To determine whether synthetic soluble liposome constructs displaying Sonic hedgehog or Delta can control NSC function. 2. To analyze whether biomimetic surfaces functionalized with Sonic hedgehog or Delta can effectively regulate NSC behavior. [unreadable] [unreadable] [unreadable]